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Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

Oncogene volume 34, pages 3305–3314 (2015)Cite this article

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Abstract

Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)–Hsp90-organizing protein (HOP) with cellular prion protein (PrPC) triggers a large number of trophic effects in the nervous system. We found that both PrPC and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I–III. High levels of PrPC and HOP were associated with greater GBM proliferation and lower patient survival. HOP–PrPC binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrPC binding site (HOP230–245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230–245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230–245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrPC–HOP engagement is a promising approach for GBM therapy.

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Acknowledgements

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 09/14027-2, 07/08410-2 and 04/12133-6) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fellowships from FAPESP (to TGS) (2009/51653-9), NGQ (2009/51751-0), BC-S (2008/55381-0), BRR (2010-13654-0, 2012/19019-0), APW-S (2010/20796-6), and from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (to APW-S) are gratefully acknowledged. We are thankful for Maria Del Mar Inda and Severino da Silva Ferreira for technical assistance. Drs Maria Dirlei Begnami, Victor Piana de Andrade and Martín Roffe contributed with helpful discussions. We thank the AC Camargo Biobank for providing the astrocytoma samples used in this study.

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Author notes

  1. M H Lopes and T G Santos: These authors contributed equally to this work.

Authors and Affiliations

  1. International Research Center, AC Camargo Cancer Center, São Paulo, Brazil

    M H Lopes, T G Santos, B R Rodrigues, N Queiroz-Hazarbassanov, A P Wasilewska-Sampaio, B Costa-Silva, F A Marchi & V R Martins

  2. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo,

    M H Lopes

  3. São Paulo, Brazil

    M H Lopes

  4. National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil

    M H Lopes, T G Santos, B R Rodrigues, N Queiroz-Hazarbassanov, A P Wasilewska-Sampaio, B Costa-Silva, F A Marchi & V R Martins

  5. Department of Pathology, AC Camargo Cancer Center, São Paulo, Brazil

    I W Cunha

  6. Inter-institutional Grad Program on Bioinformatics, Institute of Mathematics and Statistics, USP—São Paulo University, São Paulo, Brazil

    F A Marchi

  7. Department of Pathology, Federal University of Paraná, Curitiba, Brazil

    L F Bleggi-Torres

  8. Pelé Pequeno Príncipe Research Institute, Curitiba, Brazil

    L F Bleggi-Torres

  9. Department of Neurosurgery, AC Camargo Cancer Center, São Paulo, Brazil

    P I Sanematsu & S H Suzuki

  10. Department of Neurology, School of Medicine, University of São Paulo, Brazil

    S M Oba-Shinjo & S K N Marie

  11. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia,

    E Toulmin & A F Hill

  12. Ludwig Institute for Cancer Research, São Paulo, Brazil

    V R Martins

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Lopes, M., Santos, T., Rodrigues, B. et al. Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene 34, 3305–3314 (2015). https://doi.org/10.1038/onc.2014.261

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